Project Details
Projekt
Auto-regulation of the thyroid gland by classical and non-classical pathways
Applicant
Professorin Dr. Klaudia Brix
Subject Area
Endocrinology, Diabetology, Metabolism
Term
from 2012 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 221079177
Thyroid hormone (TH) target cells need to adopt mechanisms to maintain sufficient levels of TH to ensure regular functions. Interference with auto-regulative or auto-protective mechanisms against a lack or an excess of TH is a first likely cause of inadequate organ function. In the specific case of the thyroid gland itself, auto-protection is also vital for all other organs that are dependent on TH. The main objective of this project is therefore to reach a better understanding of cellular and molecular pathways underlying auto-regulation of thyroid functions. To this aim, we investigated classical regulatory mechanisms by comparing wild type mice with cathepsin-deficient animals that are characterized by altered TH generation due to impaired thyroglobulin processing. Non-classical pathways of thyroid auto-regulation were studied by analyzing TH transporters and thyronamines. Our results suggest an interplay between thyroglobulin processing and TH transporters. We propose that a TH sensing mechanism is enabled such that different TH transporters are present in specific subcellular locations in thyroid epithelial cells selectively monitoring individual steps of thyroglobulin processing and thus, the cellular TH status. Therefore our established pipeline of automated, non-biased analyses of structural and functional parameters of the thyroid gland will be employed to further analyze mice for the effects of altered thyroglobulin processing or TH translocation on thyroid function in situ. Additionally we will use an established in vitro system, consisting of FRT and FRTL-5 cells, to investigate trafficking of TH transporter proteins and to study their function under TH-clean and physiological TH conditions. We expect to substantiate our proposal that proteases and TH transporters are functionally connected. Thyronamines are derivatives of the classical TH which might also engage in thyroid regulation. It is known that the thyronamine 3-T1AM triggers the G-protein coupled trace amine-associated receptor 1 (Taar1) in vitro. We detected Taar 1 at cilia of the apical plasma membrane of cultured thyrocytes and in thyroid tissue. These results suggest the thyroid follicle lumen as the putative location of thyronamine generation and its contribution to auto-regulation of the thyroid gland by acting on Taar1 at apical cilia of thyroid epithelial cells. To elucidate such pathways by signaling studies we will incubate normal and Taar (over)-expressing thyrocytes with 3-T1AM or other known agonists in vitro. In addition, phenotyping Taar1-deficient mice will allow us to investigate the specific contribution of Taar1 to auto-regulation of the thyroid gland in situ. Finally, determination of classical and non-classical TH (the thyronome) in thyroid tissue and blood serum is timely and will help to understand metabolic availabilities of thyronamines in mice with challenged thyroglobulin processing, TH translocation, and thyronamine-responsive capabilities.
DFG Programme
Priority Programmes
